Effect Of Drugs of Abuse On Synaptic Transmission In Nucleus Accumbens

丘脑核（NAc）是一个重要的大脑区域，参与动机，介导的奖励和成瘾性质的几类滥用药物。此外，由于其在动机过程中的作用，NAc也与涉及情绪和动机改变的精神疾病有关。 因此，有必要了解这个大脑区域的基本功能，以及滥用药物如大麻，可卡因，阿片类药物和设计师药物对这个系统的作用。NAc主要由中等多刺的GABA能输出神经元（MSN）组成，其接受来自其他MSN的神经支配、来自许多其他脑区域的谷氨酸神经支配和来自腹侧中脑的多巴胺神经支配。急性，GABA和谷氨酸突触到MSN的抑制几类滥用药物，这表明这种行动可能有助于他们的奖励性质，长期暴露于药物改变了内在电路和外在输入的功能。此外，已知滥用药物会增加NAc中多巴胺（DA）的释放，这可能有助于在重复激活多巴胺能传入后观察到的兴奋性传递的长期变化。 虽然我们对NAc对行为的作用有很多了解，但对于这种突触可塑性对行为的作用机制，以及滥用药物如何改变突触过程，我们仍然知之甚少。 为了研究滥用药物在NAc中的作用，我们正在利用转基因和正常啮齿动物中的电生理学和行为分析结合光遗传学技术。 目前的实验涉及检查特定NAc输入和输出途径对行为的影响，以及通过自我管理或通过实验者交付暴露于滥用药物后这些途径的变化。当使用含有这些构建体的腺相关病毒（AAV）时，光遗传学允许选择性表达光激活蛋白，例如通道视紫红质-2（ChR 2）或盐视紫红质（Halo）。由于许多酪氨酸羟化酶阳性（TH+）VTA神经元也表达囊泡谷氨酸转运蛋白-2（VGlut-2），因此它们能够将DA和谷氨酸信号共传递至NAc。 我们发现，光激活ChR 2引起谷氨酸介导的突触EPSC在NAc壳病毒注射到几个大脑区域，发送轴突的NAc。这些EPSP的属性，然后比较通路之间针对NAc，如腹侧海马，基底外侧杏仁核和内侧前额叶皮层，并改变其功能后，暴露于大麻的精神活性成分，δ-9-四氢大麻酚（THC），在这些途径中的每一个可以进行比较。 具体来说，我们最近的工作表明，暴露于THC超过2周会导致前额叶皮层输入NAc壳显着减弱，并大大加强了来自腹侧海马和基底外侧杏仁核的输入。在NAc的输入中观察到的变化模式与在人类大麻使用者中进行的脑成像研究中的报告一致，并表明对NAc的皮质控制丧失，并且随着长期使用THC，皮质下控制增加。这对人类的认知和情感处理具有重要意义，我们假设我们发现的变化与被诊断患有大麻使用障碍的人类中观察到的行为和精神变化有关。 额外的工作包括检查NAc的输出途径与冲动行为的相关性，这些冲动行为与人类药物使用和药物寻求复发有关。 在这方面，我们将逆行追踪研究与免疫组织化学相结合，以确定参与抑制不必要行为的NAc靶向通路。 这些正在进行的研究已经开发了冲动行为的行为测定，这些冲动行为因NAc输出中断而增加。这些最近的研究表明，NAc的输出对于控制涉及有效奖励寻求策略的操作性行为以及寻求可卡因等药物的冲动非常重要。

The nucleus accumbens (NAc) is a critical brain area involved in motivation that mediates the rewarding and addictive properties of several classes of abused drugs. Additionally, because of its role in motivational processes, the NAc is also implicated in psychiatric disorders that involve alterations in mood, and motivation. Therefore, it is necessary to understand the basic function of this brain region, as well as the actions of abused drugs such as marijuana, cocaine, opioids, and designer drugs on this system. The NAc is largely comprised of medium spiny, GABAergic output neurons (MSNs) that receive innervation from other MSNs, glutamate innervation from many additional brain areas, and dopamine innervation from the ventral midbrain. Acutely, both GABA and glutamate synapses onto MSNs are inhibited by several classes of abused drugs, suggesting that this action may contribute to their rewarding properties, and long-term exposure to drugs alters the function of both intrinsic circuits and extrinsic inputs. In addition, abused drugs are known to increase the release of dopamine (DA) in the NAc, and this likely contributes to long-term changes in excitatory transmission observed following repetitive activation of glutamatergic afferents. Although much is known about the contributions of the NAc to behavior, the precise mechanisms in which such synaptic plasticity contributes to behavior, and how abused drugs alter synaptic processes remains poorly understood. To investigate the actions of abused drugs in the NAc, we are utilizing electrophysiology and behavioral analyses combined with optogenetic techniques in transgenic and normal rodents. Current experiments involve examining the influence of specific NAc input and output pathways on behavior and changes in these pathways after exposure to abused drugs by self-administration or through experimenter delivery. Optogenetics permits selective expression of the light-activated proteins, such as channelrhodopsin-2 (ChR2), or halorhodopsin (Halo) when an adeno-associated virus (AAV) containing these constructs are used. As many tyrosine hydroxylase positive (TH+) VTA neurons also express the vesicular glutamate-2 transporter (VGlut-2) they are capable of co-transmitting DA and glutamate signals to the NAc. We find that light-activation of ChR2 evokes glutamate-mediated synaptic EPSCs in the NAc shell following virus injections into several brain regions that send axons to the NAc. These EPSP properties are then compared among pathways targeting the NAc, such as the ventral hippocampus, basolateral amygdala and medial prefrontal cortex, and alterations in their function following exposure to the psychoactive component of marijuana, delta-9-tetrahydrocannabinol (THC), on each of these pathways can be compared. Specifically, our recent work shows that exposure to THC over 2 weeks causes a significant weakening of prefrontal cortical inputs to the NAc shell, and greatly strengthens inputs arising from the ventral hippocampus and basolateral amygdala. The pattern of changes observed in the inputs to the NAc are consistent with reports in brain imaging studies conducted in human marijuana users, and suggest a loss of cortical control over the NAc and an increase in subcortical control with chronic THC use. This has important implications for cognition and emotional processing in humans, and we hypothesize that the changes we have identified are related to behavioral and psychiatric changes seen in humans that are diagnosed with cannabis use disorder. Additional work includes an examination of the relevance of output pathways of the NAc to impulsive behaviors that are linked to drug use and relapse to drug seeking in humans. In this regard, we are combining retrograde tracing studies with immunohistochemistry to identify pathways targeted by the NAc that are involved in suppression of unwanted behavior. These ongoing studies have developed behavioral assays of impulsive behavior that are increased by disruption of NAc output. These more recent studies are indicating that outputs from the NAc are important for controlling operant behavior involving efficient reward seeking strategies, and in the impulse to seek drugs like cocaine.